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In three microcosm experiments, we exposed microbial communities of a natural sediment to environmentally relevant concentrations of the fungicide captan, the herbicide isoproturon, and the insecticides deltamethrin and pirimicarb. Exposure concentrations were estimated negligible concentrations (NCs), maximum permissible concentrations (MPCs), and 100 times MPC (100MPC). Experimental endpoints were microbial community respiration and biomass, bacterial activity, and denitrification. All four pesticides inhibited bacterial activity by 20 to 24% at MPC, which corresponded to concentrations in the range of µg/kg dry-weight sediment. Treatments with deltamethrin and isoproturon showed inhibiting effects on bacterial activity at NC exposures. Surprisingly, for captan, deltamethrin, and isoproturon, this inhibiting effect was not observed at 100MPC treatments. Microbial biomass was negatively effected in MPC treatments with deltamethrin and in NC treatments with isoproturon. The tested pesticides did not affect community respiration and denitrification rates. These results show that exposure to the tested pesticides may induce toxic responses in sediment microbial communities at concentrations that are predicted to be environmentally safe. [ABSTRACT FROM AUTHOR]

Under estuarine conditions, hydrophobic pesticides undergo physical/chemical partitioning into dissolved and particulate fractions of sediments. Our experimental study using 14C-chlorpyrifos (14C-CHPY) showed that sorptive associations of this common insecticide with particulate (>0.2 µm) and dissolved fractions (<0.2 µm) of sediments strongly influenced uptake, tissue absorption, and elimination in the estuarine bivalve Mercenaria mercenaria. Bivalves were fed algae mixed with particulate and dissolved fractions of 14C-CHPY-contaminated estuarine sediment particles, components of estuarine sediments (silica, humic acids), and a naturally occurring food source (phytoplankton) to quantify relative uptake, tissue absorption efficiencies, and elimination of 14CCHPY. Measurements of 14C-CHPY tissue absorption efficiencies (AE%) indicated that particle source qualities influenced much of the insecticide bioavailability. Mean tissue AE% of 14C-CHPY associated with different particulate fractions ranged from 23 to 31%, while uptake from the dissolved/colloidal forms resulted in low (7-17%) AE%. Our data indicated that 14C-CHPY is more likely to bioaccumulate through ingestion of contaminated particulate material than through filtration/ingestion of dissolved/colloidal material. The high selectivity and digestibility of algae particles by M. mercenaria, a potentially ingested food source, may play an important role in the bioavailability of chlorpyrifos in this animal. [ABSTRACT FROM AUTHOR]

The EAT-Lancet diet was created to support dietary transition towards sustainable diets. Current evidence indicates that adherence to the EAT-Lancet diet may reduce mortality risk, yet how adherence may impact dietary exposure to food contaminants remains unexplored. We aimed to estimate the association between adherence to the EAT-Lancet diet and i) all-cause, cardiovascular-, and cancer-mortality and ii) predicted dietary exposure to the following food contaminants: cadmium, methylmercury, polychlorinated biphenyls (PCBs), and pesticide residues. We used self-reported dietary data from a 96-item food frequency questionnaire of two population-based cohorts – the Cohort of Swedish Men (n = 35,687) and the Swedish Mammography Cohort (n = 32,488). The EAT-Lancet Adherence Index (EAI) was created by scoring consumption of the 14 dietary components included in the EAT-Lancet diet (totalling 0–14 points). Cox proportional hazards regression models were applied to assess the association between EAI and mortality outcomes, presented as multivariable-adjusted hazard ratios (HR) and 95 % confidence intervals (CI). Descriptive statistics were used to characterise predicted exposure to food contaminants, and the correlations between EAI and food contaminants assessed using Spearman's rank correlation. Increased adherence to the EAT-Lancet diet was associated with a lower risk of all-cause mortality (per 3-point increase in EAI: HR = 0.93; CI:0.90,0.97 and HR = 0.91; CI:0.87,0.95 for men and women, respectively) and cardiovascular-mortality (corresponding HR = 0.94; CI:0.88,1.00 and HR = 0.93; CI:0.87,1.00). No clear association was found with cancer-mortality. Increasing EAI was correlated with increased predicted dietary exposure to cadmium, methylmercury, PCBs, and pesticide residues and their median predicted dietary exposures were greater in the high adherence group, compared to the low adherence group. High adherence to the EAT-Lancet diet is associated with a reduction in risk of all-cause and cardiovascular-mortality, but also increased dietary exposure to food contaminants. [ABSTRACT FROM AUTHOR]

The development and activity of microbiota in artificial sediment may have strong implications for the fate of test compounds and the outcome of toxicity tests. In this study, we compare a number of microbial variables in the artificial sediment commonly used in toxicity testing with that of natural sediments. Bacterial abundance of artificial sediment ranged 5.7 to 7.1 x 108 cells/g wet weight, which is about two orders of magnitude lower than values commonly reported for natural sediments. Similarly, alternative estimates of microbial biomass (sum of phospholipid fatty acid, ergosterol, adenosine triphosphate) were several times lower for artificial sediment compared with natural sediment. Bacterial activity (³H-thymidine incorporation) ranged 4.0 to 7.4 pmol g-1 h-1 (or 0.062-0.113 µg C g-1 h-1) in artificial sediments, which is low compared with values commonly reported for freshwater sediments. Community respiration in artificial sediment was 34 to 93 µg CO2 g-1 d-1. Bacterial community composition assessed by terminal restriction fragment length polymorphism of polymerase chain reaction amplified 16S rRNA genes demonstrated that natural bacterial communities appear to be more diverse than their counterparts in artificial sediment. The average similarity of the microbial communities obtained by this method was less than 40%, and different operational taxonomic units appeared to dominate the artificial and natural sediment, respectively. These results and supporting data from previous studies in natural sediments suggest that the artificial sediment has a poorly developed microbial component that differs substantially from that in natural sediments. [ABSTRACT FROM AUTHOR]

Groundwater monitoring is the highest tier in the leaching assessment of plant protection products in the EU. The European Commission requested EFSA for a review by the PPR Panel of the scientific paper of Gimsing et al. (2019) on the design and conduct of groundwater monitoring studies. The Panel concludes that this paper provides many recommendations; however, specific guidance on how to design, conduct and evaluate groundwater monitoring studies for regulatory purposes is missing. The Panel notes that there is no agreed specific protection goal (SPG) at EU level. Also, the SPG has not yet been operationalised in an agreed exposure assessment goal (ExAG). The ExAG describes which groundwater needs to be protected, where and when. Because the design and interpretation of monitoring studies depends on the ExAG, development of harmonised guidance is not yet possible. The development of an agreed ExAG must therefore be given priority. A central question in the design and interpretation of groundwater monitoring studies is that of groundwater vulnerability. Applicants must demonstrate that the selected monitoring sites represent realistic worst‐case conditions as specified in the ExAG. Guidance and models are needed to support this step. A prerequisite for the regulatory use of monitoring data is the availability of complete data on the use history of the products containing the respective active substances. Applicants must further demonstrate that monitoring wells are hydrologically connected to the fields where the active substance has been applied. Modelling in combination with (pseudo)tracer experiments would be the preferred option. The Panel concludes that well‐conducted monitoring studies provide more realistic exposure assessments and can therefore overrule results from lower tier studies. Groundwater monitoring studies involve a high workload for both regulators and applicants. Standardised procedures and monitoring networks could help to reduce this workload. [ABSTRACT FROM AUTHOR]

Development of adverse outcome pathways (AOPs) for uterine adenocarcinoma can provide a practical tool to implement the EFSA‐ECHA Guidance (2018) for the identification of endocrine disruptors in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009. AOPs can give indications about the strength of the relationship between an adverse outcome (intended as a human health outcome) and chemicals (pesticides but not only) affecting the pathways. In this scientific opinion, the PPR Panel explored the development of AOPs for uterine adenocarcinoma. An evidence‐based approach methodology was applied, and literature reviews were produced using a structured framework assuring transparency, objectivity, and comprehensiveness. Several AOPs were developed; these converged to a common critical node, that is increased estradiol availability in the uterus followed by estrogen receptor activation in the endometrium; therefore, a putative AOP network was considered. An uncertainty analysis and a probabilistic quantification of the weight of evidence have been carried out via expert knowledge elicitation for each set of MIEs/KEs/KERs included in individual AOPs. The collected data on the AOP network were evaluated qualitatively, whereas a quantitative uncertainty analysis for weight of the AOP network certainty has not been performed. Recommendations are provided, including exploring further the uncertainties identified in the AOPs and putative AOP network; further methodological developments for quantifying the certainty of the KERs and of the overall AOPs and AOP network; and investigating of NAMs applications in the context of some of the MIEs/KEs currently part of the putative AOP network developed. This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2023.EN-7748/full [ABSTRACT FROM AUTHOR]

The EFSA Panel on Plant Protection Products and their Residues was requested by the European Commission, to conclude based upon available evidence if metabolites 3‐phenoxybenzoic acid (PBA) and 3‐(4′‐hydroxyphenoxy)benzoic acid (PBA(OH)), common to several pyrethroid compounds, have genotoxic properties, if they share the (neuro)toxicity profile of their parent compounds, and if evidence allows to conclude on their health‐based guidance values. Available body of evidence consisted of studies from regulatory dossiers submissions, as well as from public literature. In addition, the data gap for short‐term toxicity profile of PBA was addressed by read‐across. Assessment revealed that PBA and PBA(OH) do not raise a concern with respect to genotoxicity. As regards general toxicity, PBA and PBA(OH) have different qualitative (no neurotoxic mechanism) and quantitative (higher NOAELs) toxicity compared to the parent pyrethroid compounds. For both metabolites, acceptable daily intake (ADI) and acute reference dose (ARfD) values were derived at 0.1 mg/kg body weight (bw) per day and 1 mg/kg bw, respectively. [ABSTRACT FROM AUTHOR]

Flupyradifurone is a novel butenolide insecticide, first approved as an active substance for use in plant protection products by Commission Implementing Regulation (EU) 2015/2084. Following concerns that this substance may pose high risks to humans and the environment, the French authorities, in November 2020, asked the Commission to restrict its uses under Article 69 of Regulation (EC) No 1107/2009. To support this request, competent Authorities from France cited a series of literature papers investigating its hazards and/or exposure to humans and the environment. In addition, in June 2020, the Dutch Authorities notified the Commission, under Article 56 of Regulation (EC) No 1107/2009, of new information on flupyradifurone on the wild bee species Megachile rotundata. This notification is also referred to in the French notification on flupyradifurone. Consequently, the EFSA PPR Panel was mandated to quantify the likelihood of this body of evidence constituting proof of serious risks to humans or the environment. Therefore, the EFSA PPR Panel evaluated the likelihood of these studies indicating new or higher hazards and exposure to humans and the environment compared to previous EU assessments. A stepwise methodology was designed, including: (i) the initial screening; (ii) data extraction and critical appraisal based on the principles of OHAT/NTP; (iii) weight of evidence, including consideration of the previous EU assessments; (iv) uncertainty analysis, followed, whenever relevant, by an expert knowledge elicitation process. For the human health, only one study was considered relevant for the genotoxic potential of flupyradifurone in vitro. These data did not provide sufficient information to overrule the EU assessment, as in vivo studies already addressed the genotoxic potential of flupyradifurone. Environment: All available data investigated hazards in bee species. For honey bees, the likelihood of the new data indicating higher hazards than the previous EU assessment was considered low or moderate, with some uncertainties. However, among solitary bee species – which were not addressed in the previous EU assessment – there was evidence that Megachile rotundata may be disproportionately sensitive to flupyradifurone. This sensitivity, which may partially be explained by the low bodyweight of this species, was mechanistically linked to inadequate bodily metabolisation processes. This publication is linked to the following EFSA Journal article: http://onlinelibrary.wiley.com/doi/10.2903/j.efsa.2022.7031/full [ABSTRACT FROM AUTHOR]

Acetamiprid is a pesticide active substance with insecticidal action currently under the third renewal (AIR3) of the Commission implementing regulation (EU) No 844/2012. Following concerns that this substance may pose high risks to humans and the environment, the French authorities asked the Commission to restrict its uses under Article 69 of Regulation (EC) No 1107/2009. To support this request, competent Authorities from France cited a series of literature papers investigating its hazards and/or exposure to humans and the environment. Consequently, the EFSA PPR Panel was mandated to advise on the likelihood that body of evidence would constitute proof of serious risks to humans or the environment. Therefore, the EFSA PPR Panel evaluated the likelihood of these studies indicating new or higher hazards and exposure to humans and the environment compared to previous EU assessments.A stepwise methodology was designed, including: (i) the initial screening; (ii) the data extraction and critical appraisal based on the principles of OHAT/NTP; (iii) the weight of evidence, including consideration of the previous EU assessments; (iv) the uncertainty analysis, followed, whenever relevant, by an expert knowledge elicitation process. For human health, no conclusive evidence of higher hazards compared to previous assessment was found for genotoxicity, developmental toxicity, neurotoxicity including developmental neurotoxicity and immunotoxicity. However, due to the lack of adequate assessment of the current data set, the PPR Panel recommends conducting an assessment of endocrine disrupting properties for acetamiprid in line with EFSA/ECHA guidance document for the identification of endocrine disruptors. For environment, no conclusive, robust evidence of higher hazards compared to the previous assessment was found for birds, aquatic organisms, bees and soil organisms. However, the potential of high inter‐species sensitivity of birds and bees towards acetamiprid requires further consideration. This publication is linked to the following EFSA Journal article: http://onlinelibrary.wiley.com/doi/10.2903/j.efsa.2022.7030/full [ABSTRACT FROM AUTHOR]

EFSA asked the Panel on Plant Protection Products and their residues to deliver a Scientific Opinion on testing and interpretation of comparative in vitro metabolism studies for both new active substances and existing ones. The main aim of comparative in vitro metabolism studies of pesticide active substances is to evaluate whether all significant metabolites formed in the human in vitro test system, as a surrogate of the in vivo situation, are also present at comparable level in animal species tested in toxicological studies and, therefore, if their potential toxicity has been appropriately covered by animal studies. The studies may also help to decide which animal model, with regard to a particular compound, is the most relevant for humans. In the experimental strategy, primary hepatocytes in suspension or culture are recommended since hepatocytes are considered the most representative in vitro system for prediction of in vivo metabolites. The experimental design of 3 × 3 × 3 (concentrations, time points, technical replicates, on pooled hepatocytes) will maximise the chance to identify unique (UHM) and disproportionate (DHM) human metabolites. When DHM and UHM are being assessed, test item‐related radioactivity recovery and metabolite profile are the most important parameters. Subsequently, structural characterisation of the assigned metabolites is performed with appropriate analytical techniques. In toxicological assessment of metabolites, the uncertainty factor approach is the first alternative to testing option, followed by new approach methodologies (QSAR, read‐across, in vitro methods), and only if these fail, in vivo animal toxicity studies may be performed. Knowledge of in vitro metabolites in human and animal hepatocytes would enable toxicological evaluation of all metabolites of concern, and, furthermore, add useful pieces of information for detection and evaluation of metabolites in different matrices (crops, livestock, environment), improve biomonitoring efforts via better toxicokinetic understanding, and ultimately, develop regulatory schemes employing physiologically based or physiology‐mimicking in silico and/or in vitro test systems to anticipate the exposure of humans to potentially hazardous substances in plant protection products. This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2021.EN-6989/full [ABSTRACT FROM AUTHOR]

The EFSA Panel on Plant Protection Products and their Residues (PPR) has developed, as a self‐task mandate (EFSA‐Q‐2019‐00100), two adverse outcome pathway (AOP)‐informed integrated approach to testing and assessment (IATA) case studies to answer a developmental neurotoxicity (DNT) hazard identification and characterisation problem formulation that could support the regulatory decisions for the pesticide active substances deltamethrin and flufenacet. The IATA were developed to assess the applicability of the DNT in vitro testing battery (IVB), designed to explore fundamental neurodevelopmental processes, in the regulatory risk assessment of pesticides. For this purpose, an evidence‐based‐approach methodology was applied: 1) systematic literature review and critical appraisal of all the evidence i.e. human observational studies, in vivo data from rodent models and new approach methodologies (NAMs, i.e. in vitro studies including high‐throughput testing from IVB and zebrafish studies from the literature) for both case studies; 2) a quantitative uncertainty analysis of all the evidence using expert knowledge elicitation (EKE) and a probabilistic approach; 3) integration of all the evidence using the AOP conceptual framework. This stepwise approach resulted in the postulation of an evidence‐based AOP network for one of the case studies. A probabilistic quantification of the weight of evidence (WoE) using Bayesian network analysis allowed the assessment and the quantification of the uncertainty in the postulated AOP. The approach taken allowed conclusions to be drawn with an acceptable level of certainty in DNT hazard identification and characterisation of deltamethrin and that flufenacet is not a developmental neurotoxicant, supporting the relevance of the mechanistic understanding. The case studies show the applicability of the DNT‐IVB for hazard identification and characterisation and illustrate the usefulness of an AOP‐informed IATA for regulatory decision making. The overall activity led to improved interpretation of human data by providing a plausible mechanistic link to adverse outcomes, which would support their contextualisation in the risk assessment process. This Scientific Opinion allows the PPR Panel to draft several recommendations for the implementation of the AOP‐informed IATA methodology and of the DNT‐IVB in the regulatory risk assessment of pesticides. [ABSTRACT FROM AUTHOR]

The European Commission asked the European Food Safety Authority (EFSA) to prepare a statement on a framework for the environmental risk assessment (ERA) of transition metals (e.g. iron and copper) used as active substances in plant protection products (PPPs). Non-degradability, essentiality and specific conditions affecting fate and behaviour as well as their toxicity are distinctive characteristics possibly not covered in current guidance for PPPs. The proposed risk assessment framework starts with a preliminary phase, in which monitoring data on transition metals in relevant environmental compartments are provided. They deliver the metal natural background and anthropogenic residue levels to be considered in the exposure calculations. A first assessment step is then performed assuming fully bioavailable residues. Should the first step fail, refined ERA can, in principle, consider bioavailability issues; however, non-equilibrium conditions need to be taken into account. Simple models that are fit for purpose should be employed in order to avoid unnecessary complexity. Exposure models and scenarios would need to be adapted to address environmental processes and parameters relevant to the fate and behaviour of transition metals in water, sediment and soils (e.g. speciation). All developments should follow current EFSA guidance documents. If refined approaches have been used in the risk assessment of PPPs containing metals, post-registration monitoring and controlled long-term studies should be conducted and assessed. Utilisation of the same transition metal in other PPPs or for other uses will lead to accumulation in environmental compartments acting as sinks. In general, it has to be considered that the prospective risk assessment of metal-containing PPPs can only cover a defined period as there are limitations in the long-term hazard assessment due to issues of non-degradability. It is therefore recommended to consider these aspects in any risk management decisions and to align the ERA with the goals of other overarching legislative frameworks. [ABSTRACT FROM AUTHOR]

A retrospective cumulative risk assessment of dietary exposure to pesticide residues was conducted for chronic inhibition of acetylcholinesterase. The pesticides considered in this assessment were identified and characterised in a previous scientific report on the establishment of cumulative assessment groups of pesticides for their effects on the nervous system. The exposure assessments used monitoring data collected by Member States under their official pesticide monitoring programmes in 2016, 2017 and 2018, and individual food consumption data from 10 populations of consumers from different countries and from different age groups. Exposure estimates were obtained by means of a two‐dimensional probabilistic model, which was implemented in SAS® software. The characterisation of cumulative risk was supported by an uncertainty analysis based on expert knowledge elicitation. For each of the 10 populations, it is concluded with varying degrees of certainty that cumulative exposure to pesticides contributing to the chronic inhibition of acetylcholinesterase does not exceed the threshold for regulatory consideration established by risk managers. [ABSTRACT FROM AUTHOR]

The European Commission requested EFSA to provide scientific advice on the translocation potential by Pseudomonas chlororaphis MA342 in plants after seed treatment of cereals and peas and, if applicable, for a revision of the assessment of the risk to humans by its metabolite 2,3‐deepoxy‐2,3‐didehydro‐rhizoxin (DDR) and this based on the evidence available in the dossier for renewal of the approval. The information from other P. chlororaphis strains than MA342 was taken into account with care, because the studies available in the dossier did not confirm the identity of the strain MA342 as belonging to the species P. chlororaphis. It has been concluded that there is a potential for translocation of P. chlororaphis MA342 to edible plant parts following seed treatment till an estimated concentration up to about 105 cfu/g and some exposure can be assumed by consumption of fresh commodities. Also, production of the metabolite DDR in the plant cannot be excluded. Regarding levels of DDR in the raw agricultural commodities, exposure estimates based on the limit of quantification (LOQ) for DDR in cereals cannot be further refined while there is no information on the levels of DDR in peas in the dossier. As regards genotoxicity, DDR induced chromosomal damage; however, it was not possible to conclude whether it is through an aneugenic or clastogenic mechanism. Hence, it is not possible to draw a reliable conclusion that DDR is producing an aneugenic effect nor to determine a threshold dose for aneugenicity. Thus, it is not possible to revise the human risk assessment as regards exposure to DDR. The concerns identified in the EFSA conclusion of 2017 remain. [ABSTRACT FROM AUTHOR]

There is a concern that pesticide residues, regularly detected in foods, might pose a health risk to the consumer, but epidemiological evidence is limited. We assessed the associations between dietary exposure to a mixture of pesticide residues and mortality. Food consumption was assessed in 68,844 participants from the Swedish Mammography Cohort and the Cohort of Swedish Men, 45–83 years at baseline (1997). Concentrations of pesticide residues detected in foods on the Swedish market (1996–1998), mainly fruits and vegetables, were obtained via monitoring programs. To assess mixture effects, we summed per food item the ratios of each single pesticide mean residue concentration divided by its acceptable daily intake to create for each participant a Dietary Pesticide Hazard Index (adjusted for energy intake and expressed per kilogram of body weight). Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95 % confidence intervals (95 %CI). During 15 years of follow-up (1998–2014), a total of 16,527 deaths occurred, of which 6,238 were caused by cardiovascular disease (CVD) and 5,364 by cancer. Comparing extreme quintiles of Dietary Pesticide Hazard Index, the highest category was inversely associated with CVD mortality HR, 0.82 (95 % CI, 0.75–0.90) and with cancer mortality HR 0.82 (95 % CI 0.75–0.91). In analyses stratified by high/low Dietary Pesticide Hazard Index, similar inverse associations were observed by increasing fruit and vegetable consumption. We observed no indications that dietary exposure to pesticide residue mixtures was associated with increased mortality, nor any clear indications that the benefits of fruit and vegetable consumption on mortality was compromised. Yet, our results need to be interpreted with caution. [ABSTRACT FROM AUTHOR]

Bats are an important group of mammals, frequently foraging in farmland and potentially exposed to pesticides. This statement considers whether the current risk assessment performed for birds and ground dwelling mammals exposed to pesticides is also protective of bats. Three main issues were addressed. Firstly, whether bats are toxicologically more or less sensitive than the most sensitive birds and mammals. Secondly, whether oral exposure of bats to pesticides is greater or lower than in ground dwelling mammals and birds. Thirdly, whether there are other important exposure routes relevant to bats. A large variation in toxicological sensitivity and no relationship between sensitivity of bats and bird or mammal test‐species to pesticides could be found. In addition, bats have unique traits, such as echolocation and torpor which can be adversely affected by exposure to pesticides and which are not covered by the endpoints currently selected for wild mammal risk assessment. The current exposure assessment methodology was used for oral exposure and adapted to bats using bat‐specific parameters. For oral exposure, it was concluded that for most standard risk assessment scenarios the current approach did not cover exposure of bats to pesticide residues in food. Calculations of potential dermal exposure for bats foraging during spraying operations suggest that this may be a very important exposure route. Dermal routes of exposure should be combined with inhalation and oral exposure. Based on the evidence compiled, the Panel concludes that bats are not adequately covered by the current risk assessment approach, and that there is a need to develop a bat‐specific risk assessment scheme. In general, there was scarcity of data to assess the risks for bat exposed to pesticides. Recommendations for research are made, including identification of alternatives to laboratory testing of bats to assess toxicological effects. [ABSTRACT FROM AUTHOR]

The EFSA Panel on Plant Protection Products and their Residues was requested to establish health‐based reference values for groundwater metabolites (LM2, LM3, LM4, LM5 and LM6) of the active substance terbuthylazine based on the available evidence, unless the evidence was considered insufficient to do so. The request was accepted under the explicit circumstance that the reassessment would be made according to a different methodology than the routine methodology currently applied for the assessment of metabolites in groundwater. While for metabolites LM2, LM4 and LM5, it was concluded that the reference values for terbuthylazine are applicable, substance‐specific reference values could not be derived for metabolites LM3 and LM6. The applied threshold of toxicological concern (TTC) approach has shown that metabolites LM3 and LM6 are of potential concern for consumer health, since at least one representative groundwater leaching scenario results in exposure above the relevant threshold. Moreover, other sources of exposure to LM3 and LM6 could not be excluded with certainty. It is therefore recommended to address the specific toxicities of metabolites LM3 and LM6. [ABSTRACT FROM AUTHOR]